OBJECTIVE In Years 26-30, Research Project 2 focused on the use of somatic cell genetics to discover new genes affecting the SREBP pathway. These studies will now be carried out as a part of Research Project 1. In Years 31-35, Research Project 2 will be reconfigured to focus on the molecular mechanisms for translational control and Insig-mediated degradation of HMG CoA reductase. These mechanisms will be defined using studies in cultured cells and living animals. HMG CoA reductase is the key regulated enzyme in the mevalonate pathway, which produces essential sterol and nonsterol isoprenoids required for normal cell function (Figure 1). Reductase is subject to multivalent feedback regulation, involving control at the transcriptional and post-transcriptional levels. The transcriptional control, mediated by the sterol-regulated SREBPs, is the topic of Research Project 1.